The compound of formula (I), N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-acetamide, is a key intermediate in the preparation of halogenated pyrazolo[1,5-a]pyrimidines with high affinity for GABAA receptor as described in Patent Application EP1736475A1.

Compound (II), N-{2-fluoro-5-[3-(thiophene)-2-carbonyl-pyrazolo[1,5-a]pyrimidin-7-yl]phenyl}-N-methyl-acetamide, which was firstly described in the above patent application, is particularly useful for treating or preventing anxiety, epilepsy, sleep disorders, and insomnia, for inducing sedation-hypnosis, anesthesia, and muscle relaxation, and for modulating the necessary time to induce sleep and its duration.

In the above patent application, final compound (II) is prepared by reacting (I)
with (5-amino-1H-pyrazol-4-yl)thiophene-2-yl-methanone of formula (III)
in glacial acetic acid. In turn, intermediate (I) is prepared in two steps from N-(5-acetyl-2-fluorophenyl)-N-acetamide of formula (IV)
which is treated with an excess of N,N-dimethylformamide dimethyl acetal (NNDMF-DMA) and subsequent N-methylation of the resulting compound, N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]acetamide, of formula (V)
with methyl iodide in dimethylformamide (DMF) under an inert atmosphere at 0° C., and in the presence of sodium hydride (Preparative Example 1).
The use of hazardous reagents such as methyl iodide and sodium hydride, the special experimental conditions, as for the example the low temperature required (0° C.), and the convenience of operating under an inert atmosphere in step (V)→(I) make the process of Patent Application EP1736475A1 inadvisable for the industrial production of N-{2-fluoro-5-[3-(thiophene)-2-carbonyl-pyrazolo[1,5-a]pyrimidin-7-yl]phenyl}-N-methyl-acetamide (II). In addition, other disadvantages of this process are that key intermediate (I) from (IV) through (V) is obtained with a total yield of 40%, and HPLC purity is 94.9%.
There is, therefore, a need to provide a novel process for intermediate (I) that avoids the use of hazardous materials and truly proves to be efficient from an industrial viewpoint.
The inventors of the present invention have discovered a new process for the preparation of (I) which is more eco-friendly and easily industrializable than current methods and affords the product in high yield and purity.